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Mismatch repair deficiency testing for immune checkpoint inhibitor therapy in genitourinary malignancies
Leonid M Yermakov1, Regina Kwon1, Eric Q Konnick1
1Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA.
Abstract:
DNA mismatch repair (MMR) proteins maintain genomic stability, and their deficiency (dMMR) results in hypermutability and microsatellite instability. The U.S. Food and Drug Administration (FDA) approved the immune checkpoint inhibitor pembrolizumab for use in any dMMR cancer but did not provide guidance regarding dMMR detection. This review examines laboratory methods (immunohistochemistry, polymerase chain reaction, and next-generation sequencing) for dMMR detection, emphasizing their sensitivity, specificity, and limitations. Using the current literature, we outline considerations for when to test and which method to use when assessing MMR status in genitourinary cancers.
Insights
DNA mismatch repair (MMR) deficiency (dMMR) can make cancers more responsive to immunotherapy. This review compares lab tests for detecting dMMR in genitourinary cancers to guide treatment decisions.
Area of Science:
- Genomic stability and cancer biology
- Molecular diagnostics and biomarkers
- Oncology and cancer immunotherapy
Background:
- DNA mismatch repair (MMR) proteins are crucial for maintaining genomic stability.
- Deficiency in MMR (dMMR) leads to hypermutability and microsatellite instability, biomarkers for immunotherapy response.
- The FDA approved pembrolizumab for any dMMR cancer, but lacked specific testing guidance.
Purpose of the Study:
- To review and compare laboratory methods for detecting dMMR.
- To provide guidance on selecting appropriate dMMR detection methods for genitourinary cancers.
- To inform clinical decisions regarding immunotherapy eligibility based on MMR status.
Main Methods:
- Literature review of current diagnostic methods for dMMR detection.
- Examination of immunohistochemistry (IHC), polymerase chain reaction (PCR), and next-generation sequencing (NGS).
- Analysis of method sensitivity, specificity, and limitations in MMR status assessment.
Main Results:
- Various laboratory methods exist for dMMR detection, each with unique strengths and weaknesses.
- IHC, PCR, and NGS offer different profiles of sensitivity and specificity for identifying dMMR.
- The choice of method depends on specific clinical context and laboratory capabilities.
Conclusions:
- Accurate dMMR detection is critical for identifying patients eligible for immunotherapy like pembrolizumab.
- Understanding the nuances of different testing methodologies is essential for optimal clinical application.
- Standardized guidelines for dMMR testing in genitourinary cancers are needed to ensure consistent patient care.
